Human Immunodeficiency Virus (HIV) is a major cause of morbidity and mortality in both the developed and the developing world. HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS) in humans, which in turn allows life-threatening infections and cancers to thrive as the immune system progressively fails.
HIV infection typically occurs through the transfer of bodily fluids, such as blood, semen, vaginal fluid, pre-ejaculate, or breast milk, from one individual to another. HIV may be present within these bodily fluids as either the free virus, or as a virus present within infected immune cells. HIV-1 tends to be the most virulent form of HIV, and is transmitted as a single-stranded enveloped RNA virus which, upon entry into a target cell, is converted into double-stranded DNA by reverse transcription. This DNA may then become integrated into the host's DNA where it can reside in a latent from and avoid detection by the immune system. Alternatively, this DNA may be re-transcribed into RNA genomes and translated to form viral proteins that are released from cells as new virus particles, which can then spread further.
A drug commonly used in the treatment of HIV, and particularly HIV-1, is efavirenz (EFV). Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is widely used in highly active antiretroviral therapy (HAART). The (−)-efavirenz enantiomer is sold commercially under the trade names Sustiva™ or Stocrin™. The structure of (−)efavirenz is shown below.

Although efavirenz is effective in prolonging life expectancy in HIV suffers, there are a number of drawbacks associated with the currently available formulations of efavirenz.
Efavirenz acts on an intracellular target, so the ability of efavirenz to penetrate into and accumulate within cells is a prerequisite for effective treatment (Owen and Khoo, Journal of HIV Therapy, 2004, 9(4), 53-57). One particular problem with the current formulations of efavirenz is that the penetration of the drug into cells is variable and inadequate both within and between patients. As cellular penetration and accumulation of the drug is necessary in order to effectively treat the HIV infected cells, there is a need for formulations of efavirenz that exhibit good levels of cellular accumulation, particularly in immune cells (e.g. macrophages and CD4+ lymphocytes).
In addition, the distribution of efavirenz throughout the body is also not uniform with current efavirenz formulations, and certain target tissues and sanctuary sites, such as the brain and the testis, can suffer from poor exposure to the drug. This can lead to sub-therapeutic levels of the drug reaching certain tissues, with the consequential effect that HIV infected cells residing in these tissues may not be adequately treated. Furthermore, resistance to efavirenz is becoming an increasing problem (Goshn et al., AIDS, 2009, 11, 165-173) and exposure to sub-therapeutic levels of efavirenz in these tissues increases the risk that efavirenz-resistant strains of HIV can arise and reseed the blood. Resistant strains of HIV are also transmittable meaning that individuals can be newly infected with resistant virus. There is, therefore, a need for formulations that provide an improved distribution of efavirenz throughout the body, and in particular to sanctuary sites for the virus.
A further problem with current efavirenz formulations is that it is necessary to administer large doses of the drug each day (typically the adult dose is 600 mg per day), along with multiple other anti-HIV drugs. As a consequence, a patient will need to consume a large tablet or capsule of efavirenz, or multiple smaller dosage tablets or capsules, in order to obtain the required dosage. This can inevitably lead to problems with patient compliance. Furthermore, efavirenz treatment is also associated with a number of adverse side effects, which represent a major problem for patients, especially over prolonged periods (Dahri and Ensom, Clin Pharmacokinet, 2007, 46(2), 109-132; Letendre et al, Conference Highlights—Neurologic Complications, 2010, 18(2), 45-55; Maggi et al, J. Antimicrob. Chemother., 2011, 66, 896-900). For these reasons, there is a need for more effective formulations of efavirenz, which in turn may enable the required dosage of efavirenz to be lowered. Lower doses could have an effect on the number and/or size of the tablets/capsules that need to be consumed by the patient, as well as prevalence of the adverse side effects.
There is also a need for dosage forms that permit the dosage to be easily varied on a patient-by-patient basis, depending on factors such as the age (including paediatric dosing) and weight of the patient, as well as the severity and stage of the infection.
It is therefore an object of the present invention to provide improved formulations of efavirenz that address one or more of the drawbacks associated with the current efavirenz formulations.
In particular, it is an object of the invention is to provide efavirenz formulations exhibiting good cell penetration and a more optimum and effective distribution throughout the body.
Another object of the present invention is to provide efavirenz formulations with a high drug loading.
Another object of the present invention is to provide efavirenz formulations which permits lower overall dosage of efavirenz in HIV treatments.